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Biomedical subjects

A Schwartz

Publications and source records attributed to A Schwartz.

At least 19 recordsLinked to original sources
PubMed1992

Molecular and cellular aspects of calcium channel antagonism.

Calcium fluxes play a key role in controlling many physiologic processes and responses in the body. The past few years have witnessed major advances in understanding of L-type calcium channels and their blockade with calcium channel antagonists. The L-type calcium channels comprise 5 subunits termed alpha 1, alpha 2, beta, gamma, and delta. Elucidation of the mechanisms of action of the calcium channel antagonists has been advanced by cloning and genetic manipulation of these subunits. The alpha 1 subunit appears to be responsible for channel opening and voltage dependency, and it contains receptors for calcium channel antagonists; these geographically distinct receptors correspond to each of the 3 different chemical classes of antagonists, exemplified by diltiazem, nifedipine, and verapamil. Diltiazem appears to have an inhibitory effect on mitochondrial sodium-calcium exchange that is unique among calcium channel antagonists. Preliminary data suggest that a diltiazem-specific receptor also exists in the endothelium. It appears, therefore, that despite advances in the understanding of L-type calcium channels, much remains to be learned about other possible receptors for the calcium channel antagonists.

Calcium Channel Blockers↗
PubMed1992

Evidence for the existence of RNA of Ca(2+)-channel alpha 2/delta subunit in Xenopus oocytes.

Ba(2+)-currents (IBa) through voltage-dependent Ca(2+)-channels were studied in Xenopus oocytes injected with RNA from several excitable tissues, using the two-electrode voltage-clamp technique. Previous studies have shown that the expression of cardiac Ca(2+)-channels can be suppressed by an hybrid-arrest procedure that includes co-injection of the tissue-derived RNA with an 'antisense' oligonucleotide complementary to a part of RNA coding for the Ca(2+)-channel alpha 1 subunit. In this study, this method was used to investigate the role of the alpha 2/delta subunit. Co-injection of RNA extracted from either rabbit heart, rat brain or rat skeletal muscle (SkM) with 'antisense' oligonucleotides complementary to the alpha 2/delta subunit RNA did not substantially affect the expression of IBa in the oocytes. Using the Northern blot hybridization method, it was shown that native oocytes contain large amounts of alpha 2/delta subunit RNA of Ca(2+)-channel. It is proposed that te oligonucleotide treatment fails to eliminate the alpha 2/delta RNA because of the vast excess of endogenous alpha 2/delta RNA. These results impose a limit on the use of the hybrid-arrest method.

Animals↗
PubMed1992

Distortions induced in DNA by cis-platinum interstrand adducts.

A 22 base pair double-stranded oligonucleotide containing a unique interstrand adduct resulting from chelation of the two guanine residues within the central sequence d(TGCT/AGCA) by a cis-platinum residue has been studied by means of gel electrophoresis, chemical probes, and molecular mechanics. The anomalously slow electrophoretic mobility of the multimers of the platinated and ligated oligomers suggests that the platinated oligonucleotide is bent. The two cytosine residues (complementary to the platinated guanines) are hyperreactive to hydroxylamine, indicating a large exposure of the two bases to the solvent. The adduct does not induce a local denaturation within the flanking sequences since the adenine residues are not reactive with diethyl pyrocarbonate. This is confirmed by the nonreactivity of the complementary T residues with osmium tetraoxide. These results and the molecular mechanics modeling suggest that the interstrand adduct bends the double helix by approximately 55 degrees toward the major groove, that the double helix conserves its average twist angle, and that the distortion induced by the adduct is localized at the platinated sequence d(GC/CG).

Base Sequence↗
PubMed1992

Mutually exclusive exon splicing of the cardiac calcium channel alpha 1 subunit gene generates developmentally regulated isoforms in the rat heart.

Several clones were isolated from a rat genomic library in order to further characterize a region of variability within the third membrane-spanning region of the fourth motif (IVS3) of the L-type voltage-dependent calcium channel. We report here that this diversity arises from alternative splicing of a primary transcript containing a single pair of adjacent exons each encoding a unique sequence for the IVS3 region. Definitive proof of a mutually exclusive splicing mechanism was obtained by genomic mapping of flanking upstream and downstream exons and by extensive sequence analysis of the relevant exon/intron boundaries. S1 nuclease protection experiments revealed that both variant forms of the IVS3 were equally expressed in newborn and fetal rat heart, whereas only a single isoform predominated in adult rat heart. The results demonstrate the existence of an important developmentally regulated switch mediated by alternatively spliced exons in cardiac tissue at a time when major changes in excitation occur.

Amino Acid Sequence↗
PubMed1992

Native-type DHP-sensitive calcium channel currents are produced by cloned rat aortic smooth muscle and cardiac alpha 1 subunits expressed in Xenopus laevis oocytes and are regulated by alpha 2- and beta-subunits.

Native tissue-like L-type voltage-dependent calcium channels (L-VDCC's) were expressed by in vitro transcribed cRNA injection of rat aorta or rabbit cardiac alpha 1 subunit into Xenopus laevis oocytes. Co-injection of VSM-alpha 1 with the cloned skeletal muscle beta-subunit (SK-beta) of the L-type VDCC significantly increased the expressed peak current amplitude without significant changes in kinetics. Similar results were obtained by co-injection of cardiac alpha 1 (DSHT-alpha 1) the cloned skeletal alpha 2-subunit (SK-alpha 2) or with SK-beta. The oocytes co-expressing cRNA's retained L-type VDCC pharmacology.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Beta-subunit expression is required for cAMP-dependent increase of cloned cardiac and vascular calcium channel currents.

In contrast to vascular smooth muscle (VSM), cAMP-dependent phosphorylation increases L-type voltage dependent Ca(2+)-channel (L-VDCC) activity in heart. To investigate whether this difference depends on the tissue-specific alpha 1-subunit of the L-VDCC or its regulation by other subunits, we used a Xenopus laevis oocyte expression system. Injection of cAMP into oocytes expressing cardiac alpha 1 or VSM alpha 1 alone had no effect on L-VDCC activity. However, cAMP increased L-VDCC activity 2-fold in oocytes co-expressing cardiac alpha 1 or VSM alpha 1 with the skeletal muscle beta-subunit. These results suggest that the presence of the beta-subunit is required for cAMP-mediated increase of L-VDCC activity and that the characteristics of tissue-specific beta-subunits may explain differential regulation of L-VDCC activity.

Animals↗
PubMed1992

Magnetic resonance imaging follow-up in Creutzfeldt-Jakob disease.

The history of a 67-year-old woman with histologically proven Creutzfeldt-Jakob disease (CJD) is presented. Before typical clinical and neurophysiological signs of CJD developed, magnetic resonance imaging (MRI) showed slightly enhanced signal intensity of the caudate nuclei and putamina in T2-weighted and proton density images, corresponding to spongiform degeneration in neuropathological examination. Five weeks later characteristical progressive cortical atrophy was demonstrated by follow-up MRI.

Aged↗
PubMed1992

Racial differences in cancer of the male breast--15 year experience in the Detroit metropolitan area.

Characteristics of cancer of the male breast were evaluated in a population based review of 244 cases identified retrospectively through the Metropolitan Detroit Cancer Surveillance System (MDCSS) between 1973 and 1987. The mean age at diagnosis was 65 years and median survival time, 44 months. There were no apparent time trends in incidence for either white or black men from 1973 through 1987. Modified radical mastectomy was the most common surgical procedure, while simple and radical mastectomy declined in popularity over time. Cox's proportional hazards regression model was used to test the simultaneous effects of age, race, stage, and treatment on survival. Men older than 65 at diagnosis had a greater risk of dying than men under 65 (RR 1.52, 95% confidence interval, 1.01-2.28). Survival was significantly worse for men who presented at a more advanced stage; regional versus localized (RR 2.19, 95% confidence interval, 1.39-3.45) and remote versus localized (RR 4.31, 95% confidence interval 2.26-8.23). Race had no significant effect on survival in men with breast cancer in the Detroit Metropolitan Area.

Adult↗
PubMed1992

The beta subunit controls the gating and dihydropyridine sensitivity of the skeletal muscle Ca2+ channel.

The skeletal muscle (SKM) L-type Ca2+ channel is composed of a central subunit designated alpha 1, which contains the pore and the dihydropyridine (DHP) binding domains and three associated subunits, alpha 2/delta, beta, and gamma, which influence the activity of the SKM alpha 1. Coexpression of SKM alpha 1 and SKM beta in stably transfected mouse L cells results in a dramatic increase in DHP binding accompanied by fast gated Ba2+ currents. We report here that this "SKM alpha 1 beta-related phenotype" can be converted upon intracellular trypsin treatment into a slowly inactivating, DHP sensitive "SKM alpha 1 phenotype." These observations indicate that current amplitude, fast inactivation, and DHP sensitivity are modulated by an interaction of SKM alpha 1 and SKM beta on the internal side of the membrane.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

[MR angiography of the vertebrobasilar circulatory area: the potential uses of the saturation technic to determine the direction of the flow].

MR angiography (MRA) combined with selective saturation techniques has proved to be a reliable method for the determination of flow direction and vascular supply at the level of the circle of Willis. We describe its application to the vertebrobasilar system (VBS) in ten volunteers and five patients with abnormal findings. In one patient with postsurgical stenosis of the brachiocephalic artery, reverse flow of the vertebral artery (VA) was demonstrated. Collateral blood flow from the anterior circulation over the posterior communicating arteries was shown in three patients with bilateral vertebral or proximal basilar artery occlusion. Due to increase of pressure during contrast injection into the contralateral VA, DSA showed reverse flow of a dissected VA in one patient. MR flow determination as well as TCD proved antegrade flow. All results correlated with both DSA and transcranial Doppler (TCD). The technique is little time consuming and is a promising add-on examination to conventional and MRA imaging of the VBS.

Adult↗
PubMed1992

Dehydroepiandrosterone (DHEA) and synthetic DHEA analogs are modest inhibitors of HIV-1 IIIB replication.

Down-regulation of Epstein-Barr virus (EBV) induced transformation of human lymphocytes in vitro by dehydroepiandrosterone (DHEA), a naturally occurring human steroid secreted by the adrenal gland has been demonstrated. This article reports on the effects of DHEA and its novel synthetic analogs 16 alpha-fluoro-5-androsten-17-one (8354) and 3 beta-hydroxy-16 alpha-fluoro-5 alpha-androstan-17-one (OH8356) on human immunodeficiency virus (HIV-1) replication. Treatment with DHEA, 8354, or OH8356 resulted in a modest down-regulation of HIV-1 replication in phytohemagglutinin-stimulated peripheral blood lymphocytes as measured by syncytia formation, release of p24 antigen, and accumulation of reverse transcriptase activity. DHEA and 8354 also reduced syncytia formation in HIV-1-infected SupT1 lymphoblasts. DHEA and synthetic analogs of DHEA, which have been shown previously to have antiproliferative effects, now are shown to reduce HIV-1 replication. DHEA or synthetic analogs of DHEA could provide an alternative and/or adjuvant for HIV-1 infection.

Androstenes↗
PubMed1992

Diminished in vitro production of interleukin-1 and tumor necrosis factor-alpha during acute visceral leishmaniasis and recovery after therapy.

Disturbance of T cell-mediated immunity has been reported in acute visceral leishmaniasis (AVL). In a study of 16 patients with AVL, defective production of interleukin-1 (IL-1) by peripheral blood mononuclear cells was demonstrated in response to leishmania antigens, heat-killed Listeria organisms, and lipopolysaccharide when compared to posttherapy values or controls. This global defect in IL-1 production was corrected after successful therapy. Twelve of 16 patients responded with a greater than or equal to 2.5-fold increase in IL-1 production that correlated with clinical cure, P less than .01. Depressed production of tumor necrosis factor (TNF) was leishmania antigen-specific and similarly recovered after therapy. In vitro TNF production during the follow-up period did not correlate with clinical status but high serum levels were associated with AVL. Since T cells are activated by processed antigens presented on class II major histocompatibility molecules and by newly synthesized IL-1, defective IL-1 production may contribute to the immunosuppression observed in AVL.

Acute Disease↗
PubMed1992

Active and passive electrical properties of isolated canine cardiac Purkinje fibers under conditions simulating ischaemia: effect of diltiazem.

The effect of a calcium channel blocker diltiazem on the electrical properties of canine Purkinje fibers superfused in a milieu similar to that occurring in acute myocardial ischaemia was studied. Action potential parameters, passive electrical properties, and conduction velocity were measured using conventional microelectrode techniques. Superfusion with glucose-free Tyrode's solution containing 9 mM K+, gassed with 100% N2 at pH = 6.5 ('ischemic solution') significantly reduced the maximal diastolic potential, action potential duration, maximal upstroke velocity, conduction velocity and length constant, while input resistance and longitudinal resistance were elevated and membrane resistance remained unchanged. Diltiazem (1 microM) alone reduced only the action potential duration, while all other parameters were unaffected. Pretreatment with diltiazem did not fully prevent the effects of ischemic superfusion; however, the ischaemia-induced decrease in length constant was not significant in the presence of diltiazem. In addition, the increase in longitudinal resistance during ischaemia was significantly reduced following diltiazem pretreatment. This decrease in longitudinal resistance may contribute to the improvement of ischaemia-induced conduction delay observed in intact animals and may be related to a reduction of ischaemia-induced increase in intracellular free Ca2+.

Action Potentials↗
PubMed1992

Molecular biology of the calcium antagonist receptor.

The calcium channel plays a key role in controlling many physiological processes in the body. Drugs that block the calcium channel have proven clinically effective for the treatment of a multitude of cardiovascular disorders. The elucidation of the precise mechanism of action of these drugs involves cloning the calcium channels on which they act. Genetic manipulation of these cloned channels is beginning to reveal the binding sites for the calcium channel blocking drugs and may lead to the development of more specific agents.

Animals↗
PubMed1992

Spontaneous vertebral artery dissection initially mimicking myocardial infarction.

BACKGROUND AND PURPOSE: Vertebral and carotid artery dissections may present with very different signs and symptoms, making early recognition difficult. However, diagnosis should be established as soon as possible to prevent unnecessary diagnostic investigations and to institute adequate treatment. CASE DESCRIPTION: A 46-year-old man presented with severe intermittent pain of his left upper arm and general discomfort. During extensive cardiological evaluation for suspected myocardial infarction, a severe brain stem syndrome occurred. Ultrasound Doppler studies detected vertebral artery dissection, which was confirmed by angiography. CONCLUSIONS: The unusual initial presentation of vertebral artery dissection delayed an early diagnosis and adequate treatment. Because noninvasive methods are available today, their applications are recommended in similarly uncharacteristic circumstances.

Aortic Dissection↗
PubMed1992

Facial and trigeminal neural dysfunction by a primary cutaneous squamous cell carcinoma: MRI and clinicopathologic correlates.

Carcinomatous neural infiltration and subsequent neural dysfunction are phenomena associated with the facial nerve and parotid gland tumors, particularly adenoid cystic carcinoma. The association of primary cutaneous squamous cell carcinoma (PCSCC) with these phenomena is not as well recognized, especially with respect to the involvement of the trigeminal nerve. By presenting the case history of a man who successively developed facial and trigeminal neural dysfunction after Mohs chemosurgery of a PCSCC, this paper documents histologically the occurrence of such neural invasion, and illustrates the utility of gadolinium-enhanced magnetic resonance scanning in patient management.

Carcinoma, Squamous Cell↗